Cisplatin is an effective anticancer drug that is used clinically worldwide. Toxic side effects associated with the clinical use of this drug were the impetus for the development of the second-generation platinum chemotherapeutic agent, carboplatin These two drugs operate by the same mechanism. The labile ligands of the coordination complexes, chloride for cisplatin and 1,1-cyclobutanedicarboxylate (CBDCA) for carboplatin, are displaced by water or other biological nucleophiles, and the reactive cis-diammineplatinum(II) moiety binds to nuclear DNA. The resulting platinum-DNA adducts ultimately lead to cell death through transcription inhibition and the ensuing downstream effects. Since cisplatin and carboplatin bear the same NH3 non-leaving group ligands, the nature of the resulting DNA adducts are the same, and therefore the drugs exhibit the same spectrum of activity. Carboplatin, however, is significantly less toxic than cisplatin. The typical patient dose for carboplatin is approximately ten times greater than that of cisplatin (400 mg/m2 versus 40 mg/m2), and the dose-limiting toxic side effect of carboplatin is myelosuppression in contrast to nephrotoxicity, which is dose-limiting for cisplatin treatment. These important clinical differences between cisplatin and carboplatin indicate that the leaving group ligands play an integral role in modulating toxic side effects. Modifications of the leaving group ligands may lead to new platinum anticancer drug candidates.
Accordingly, improved compositions and methods are needed.